Glucagon Regulates Energy Balance via FGF21 Signaling in the Brain

Abstract

Glucagon is an essential regulator of glucose and lipid metabolism that also promotes weight loss. Thus, novel therapeutics that stimulate glucagon‐receptor (GCGR) signaling are promising targets for treatment of obesity and diabetes; however, the mechanism(s) underlying these effects are yet to be fully elucidated. We previously identified that hepatic glucagon signaling increases the secretion of Fibroblast Growth Factor 21 (FGF21), a fasting hormone that regulates energy balance. We have recently observed that mice deficient for liver Fgf21 are partially resistant to the anti‐obesity effects of GCGR agonism, implicating hepatic FGF21 as an essential component of glucagon’s weight‐loss effects. FGF21 signals through the canonical FGF‐receptors coupled with an obligate co‐receptor (bKlotho, Klb). Expression of KLB, and therefore FGF21 signaling, is limited to adipose tissue, liver, and brain, specifically within the suprachiasmatic nucleus (SCN) of the hypothalamus and the hindbrain. The hypothalamus is a critical regulator of energy balance; thus, we hypothesized that the anti‐obesity action of the glucagon‐FGF21 system signals through a central mechanism. To test this hypothesis, we generated mice with neuronal Klb deficiency (Klbflox x Synapsin1Cre: KlbΔCNS). KlbΔCNS mice are less susceptible to diet‐induced obesity than control mice (p<0.01), with no differences in food intake or energy expenditure. Following chronic GCGR activation via the selective GCGR agonist IUB288, KlbΔCNS mice exhibit a partial reduction in body weight (11%) in comparison to control mice (18%) (p<0.001), suggesting that FGF21 mediates glucagon’s anti‐obesity properties through central action. Similar to the congenital knockout, wildtype mice treated with a selective KLB antagonist via intracerebroventricular administration also exhibited partial reductions in body weight following chronic IUB288 treatment. Consistent with GCGR‐stimulated, neuronal FGF21 signaling, we found that neuronal activation, measured via cFos expression, was increased in the SCN following IUB288 injection. To further interrogate SCN‐specific FGF21 signaling, we generated mice with SCN‐specific Klb deficiency (KlbΔSCN) via targeted adenoviral Cre recombinase induction. KlbΔSCN mice display an increase in food intake, body, and fat mass compared to control mice. Changes in food intake were associated with an increase in both light‐ and dark‐phase feeding for KlbΔSCN mice compared to controls (p<0.001). Future studies will aim to continue to interrogate SCN‐specific FGF21 signaling via the pharmaceutical antagonist and the KlbΔCNS model. Taken together, these data suggest that 1) KLB/FGF21 signaling of the SCN is critical for normal energy balance and 2) glucagon mediates part of its anti‐obesity properties through FGF21‐KLB signaling in the CNS. In sum, these findings provide insight for future treatments against obesity and the metabolic syndrome.Support or Funding InformationThe project described was supported by the NIH grant 1R01DK112934.